In 2001, Nishimoto and colleagues identified humanin (HN), a novel 24-amino-acid peptide encoded from the 16S ribosomal RNA region of the mitochondrial DNA, and described it to be a potent neurosurvival factor capable of antagonizing Alzheimer's disease-related cell death insults (Hashimoto et al., Proc Natl Acad Sci USA, 98: 6336-41 (2001)). Humanin has also been described as a Bax antagonist that induces survival in various cancer cells (Guo et al., Nature, 423: 456-61 (2003)) and as an IGFBP-3 partner that antagonizes the apoptotic actions of IGFBP-3 on cancer cells (Ikonen et al., Proc Natl Acad Sci USA, 100:13042-13047 (2003)). Additional work has indicated that humanin is a wide spectrum survival factor (Nishimoto et al., Trends Mol Med., 10:102-5 (2004)), but its exact mechanism of action remains unclear.
The humanin cDNA shares complete identity with the mitochondrial 16S rRNA gene but spans only about half the length of the ribosomal RNA. Humanin transcripts of mitochondrial origin are present in kidney, testis, brain, and the gastrointestinal tract. Interestingly, humanin is highly conserved among species (between 90-100% homology), including lower organisms.
Novel mutants and analogs of humanin with enhanced potency have been described, including HNG (S14G) (Hashimoto et al., J. Neurosci., 21: 9235-9245 (2001) and Terashita et al., J. Neurochem., 85: 1521-1538 (2003)), HNG-F6A (non-IGFBP-3 binding) (Ikonen et al., Proc Nat Acad Sci., 100: 13042-13047 (2003)) and colivelin (hybrid peptide containing partial sequences of HN and ADNF9). Humanin and its analogues and derivatives have shown therapeutic potential for an array of diseases including Alzheimer's disease, diabetes and kidney failure.